Evaluation and Management of Head and Neck Cancer in Patients with Fanconi anemia

David I. Kutler, M.D., F.A.C.S. Residency Site Director – Weill Cornell Medical Center

Associate Professor Division of Head and Neck

Department of Otolaryngology-Head and Neck Surgery

Outline • Definition of squamous cell carcinoma of the head

and neck • Incidence in FA patients compared to non-FA

population • Characteristics of FA squamous cell carcinoma • Prevention of SCC in FA patients • Surveillance recommendations for SCC in FA

patients • Treatment of SCC in FA patients

Head and Neck Cancer - 2013 New Cases vs. Deaths

CA 53(1):5-26, 2003

19,400

9,500 8,300

5,200 3,800 2,000

Oral Cav Larynx Pharynx

Head and neck cancer rates

United States Global

Mortality from head and neck cancer

United States Global

Head and Neck Cancer

• Involved mucosal surfaces of upper aerodigestive tract – Diverse anatomical loci for involvement

• Nasopharynx/paranasal sinuses • Oral cavity • Oropharynx • Larynx • Hypopharynx

Histology

SCCa Minor Salivary Melanoma Lymphoma Sarcoma

95%

Oral Pre-Malignant Lesions

• Leukoplakia: “white plaque” – Leukoplakia is a premalignant lesion found in the oral cavity. – The chance of transformation into oral squamous cell carcinoma varies

from almost 0% to about 20%, and this may occur over 1 – 30 years.

Oral Pre-Malignant Lesions

• Erythroplakia “red plaque” – Far less common than leukoplakia – Much greater probability (91%) of showing signs of dysplasia or

malignancy at the time of diagnosis. – Such lesions have a flat, macular, velvety appearance and may be

speckled with white spots representing foci of keratosis.

Oral Pre-Malignant Lesions

• Oral dysplasia • Precursor lesions of the upper aerodigestive tract • Increased likelihood of progressing to squamous cell

carcinoma. • Presence of architectural and cytological changes:

Progression from hyperplasia to cancer

Squamous Cell Carcinoma

• Squamous cell carcinoma (SCC) of the head and neck – Irregular ulcers with raised margins – May be exophytic, infiltrative or verrucoid – Mimic benign lesions grossly

Squamous Cell Carcinoma

Squamous Cell Carcinoma

Squamous Cell Carcinoma

Clinical appearance

Factors predisposing to head and neck cancer

• Tobacco/alcohol exposure • Betel nut • Viruses (HPV/EBV) • Genetic predisposing syndromes

– Li Fraumeni – p16 – Fanconi’s anemia

Tobacco & Alcohol- Risk for head and neck cancer

Never smoker

>1ppd

<1ppd

00.10.20.30.40.50.60.70.8

Never drinker 1-2drinks/day

>2 drinks/day

Prognostic factors

• Site • Size (T-stage) • Location (Anterior vs. Posterior) • Cervical node status • Histology (size, grade, depth of invasion,

host/tumor interface)

Tumor location and survival

0 20 40 60 80 100

Lip

Ant. Tongue

Gingiva

Floor of Mouth

Hard Palate

Buccal Mucosa

Tonsil

Base of Tongue

Soft Palate

Pharynx

Hypopharynx

% Survival Farr and Arthur (MSKCC:1955

TNM Stage and survival

0

10

20

30

40

50

60

70

80

90

Stage I Stage II Stage III Stage IV

% at Presentation Survival

Head and Neck Squamous cell carcinomas

• Surgery

• Radiotherapy

• Chemotherapy

•

Head and neck cancer Multimodality treatment

• Surgical oncology

• Radiation oncology

• Medical oncology

• Endocrinology • Nuclear medicine

• Dental and prosthetics

• Plastic & reconstructive surgery

• Psychiatry

• Nutrition

• Nursing • Diagnostic radiology

• Pathology

New Cancer Appearance after Treatment of H&N Primary

0

5

10

15

0 1 2 3 4 5

%/Y

r

Year

Local Recurr Neck Recurr Distant Mets 2nd Primary

Case Report • 33 year old FA male with a history of a BMT, who has a

long history of oral leukoplakia, erythroplakia and oral dysplasia diffusely covering his oral epithelium.

• He was diagnosed with a left buccal squamous cell carcinoma, which developed within an area of erythroplakia. He underwent a resection of the buccal region and left neck dissection.

• He continued to have diffuse areas of both leukoplakia and erythroplakia.

• 7 years later, he developed a second left buccal squamous cell carcinoma and recently underwent re-resection of the buccal region.

Incidence in FA patients compared to non-FA population

Time to Squamous Cell Carcinoma (in years)

Cum

ulat

ive

Inci

denc

e

0 10 20 30 40 50

0.0

0.2

0.4

0.6

0.8

1.0

21% incidence by age 40

SEER population Expected incidence: 0.038%

FA population Cumulative incidence: 19%

Standardized Incidence Ratio (SIR) = 500 (95% CI: 300-781, p<0.0001).

Characteristics of FA associated squamous cell carcinoma

FA Gen. Pop.

• Age- range 15 to 49 50-60’s median 31yr. 53yr. • Female: male 2:1 1:2

• Tob/ EtOH use 16% >85%

Anatomic distribution of HNSCC

Oral cavity SCC : 65% vs. 27%

SEER population

Oropharynx 24%

Oral Cavity 27%

Larynx 41%

Hypopharynx 8%

FA-associated HNSCC

Oropharynx 10%

Hypophar. 10%

Larynx 10%

Unknown 5%

Oral Cavity 65%

TNM staging

0

10

20

30

40

50

60

70

Stage 1 Stage 2 Stage 3 Stage 4

FA Gen. Pop

Per

cent

Hoffmann et al. Arch Oto. 199

Prevention

• Tobacco/alcohol avoidance –Second hand smoke

• Role of HPV –Vaccination

HUMAN PAPILLOMA VIRUS AND FANCONI ANEMIA

CONTROVERSIAL TOPIC

HPV positivity FA associated SCC vs. control SCC

HPV +

HPV -

HPV +

HPV -

83% HPV Positive N=25

36% HPV Positive N=50

FA-associated SCC Normal control SCC

P<0.001

Normal control SCC

Types of HPV identified in FA-associated tumors

HPV type 16

HPV type 18 HPV type 52

HPV type 16

HPV type 67HPV type 33

FA-Associated

Human Papillomavirus

• HPV-positive head and neck squamous cell carcinoma

–Distinct Disease Entity? –Even though role of HPV in FA is

controversial, it is an important risk factor in the general population.

Biology of Human Papillomavirus

• HPV is a small DNA virus – First identified in 1949 – 120 genotypes of HPV – Infect exclusively basal epithelial cells in the mucosa or skin

• Replication – Occurs within the nucleus of the infected cell – Dependent on the S-phase for entry – Requires DNA machinery to replicate

Biology of Human Papillomavirus

• HPV subtypes divided into:

Low-risk – HPV-6 and HPV-11

High-risk (15 high-risk types are known) – HPV-16, -18, -31, - 33, -35

• Each HPV type is associated with a specific clinical lesion • Cutaneous types: common wart • HPV-5 and -8: SCC of the skin • HPV-6 and -11 (low risk): benign lesions (anal warts or oral papillomas) • HPV -16, -18, -31, -33 and -45 (high risk): SCC of the mucosal regions

• HPV 16 is the most common type detected in oropharyngeal cancer – 90-95% of the HPV positive tumors.

Biology of Human Papillomavirus

HPV genome

• Small double stranded circular DNA • 8000 base pairs • Early Regions (E1-8)

– Transcription, plasmid replication and transformation.

• Late Regions (L1 and L2) – Regulatory elements for transcription and

replication

HPV genome

p53

Propose mechanisms of HPV carcinogenesis

Two HPV viral proteins – E6 and E7 can incorporate into genome and inactivate p53 or retinoblastoma (Rb) tumor suppressor genes by increased degradation.

HPV E6

E7 HPV Rb

Mechanism of carcinogenesis

• Disruption of p53 pathway – Uncontrolled cell cycle progression – Usually mutated in HPV negative tumors – Usually not mutated in HPV positive tumors, but increase degradation

leading to functional loss.

• Disruption of the pRB pathway – Failure of inhibition of E2F – Loss of cell cycle control – Upregulation of p16

• Identified by immunohistochemistry in HPV + tumors • Very high correlation (>90%) - ? surrogatemarker

Mechanisms of HPV carcinogenesis

HPV vaccine

• Based on recombinant expression and self assembly of the major capsid protein, L1 – Gardasil (Merck & Co.)- targets subtypes 6, 11, 16,

18 – Cervarix (GSK) – targets subtypes 16 and 18

• Vaccines significantly decrease the incidence of persistent HPV16 and HPV 18 infections in cervical dysplasia.

HPV vaccine

• Designed to initiate protective immunity against HPV -6, -11, -16 and -18 – Humoral immune response – Efficacy through 5 years (booster ?) – Prevents HPV infection in unexposed patients. – No biologic role for treatment of existing HPV-

associated OPSCC

HPV vaccine and oral cancer

• Animal models immunized against HPV16 have shown a reduction in the development of HPV-oral lesions.

• Further studies are coming.

Treatment of SCC in FA patients

Introduction

Head and neck procedures – Large surgical incisions – Large amount of tissue dissection – Surgical complications – Post-operative morbidity

da Vinci System

da Vinci System

da Vinci Robotic Surgery

Surgery

Radiation Therapy

• 12 Fanconi anemia patients (7 male, 5 female) underwent radiation threapy.

• Average radiation dose was 5242 cGy (range 2500 to 7020).

• The most common toxicities: – High-grade mucositis (9/12) – Dysphagia (8/12) – Pancytopenia (6/12). – Other significant complications included esophageal stenosis,

laryngeal edema, and wound breakdown.

Radiation Therapy

• Radiotherapy could not be completed in 5/12 cases.

• Overall 8/12 patients died, 4 during the course of radiation.

• Radiation should be used for high stage tumors and should be administered by physicians with experience treating FA patients.

Adjuvant therapy

• 3 patients received chemotherapy – Adjuvant chemo\XRT 1 patient – Primary treatment alone 1 patient – Chemo\XRT for recurrence 1 patient

Impact of secondary malignancies

• 12 of 19 (63%) developed multiple malignancies during their lifetime.

• 5 patients had >2 malignancies

0

10

20

30

40

50

60

70

FA Gen Pop Leon, et al. Head & Neck 1999

0

10

20

30

40

50

60

H&N Lung Esoph Skin GU/Anus Other

FA Gen Pop

Location of Second Primary

Outcome-More aggressive disease

• 10/19 (52%) had recurrence of their tumor with median disease-free interval of 10 mos. – PATTERNS OF RECURRENCE SIMILAR TO GP – Local recurrence: 7 patients – Regional recurrence: 6 patients – Distant metastases: 1 patient

• 5 of 7 stage I patients recurred locoregionally

• 14/19 (73%) died from all causes. • 11/19 (58%) died with disease.

Overall survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 Pr

opor

tion

Surv

ivin

g

0 10 20 30 40 50 60 70

Follow-up time (months)

2-year OS: 48% vs. 70% 5 year OS: 27% vs. 63%

Hoffmann et al. Arch Oto. 199

Treatment approach

• EARLY DETECTION • Surgery is the preferred treatment • Radiation can be used with care • Chemotherapy in very limited circumstances • ? Need for modification of treatment (use non-

DNA damaging chemo modalities) • Very close surveillance

Surveillance recommendations for SCC in FA patients

• Routine head and neck screening

– Role of qualified examiner – Age of onset (12-14 years) – Frequency- Biannual – Caveats

• Increase frequency to every 3 months (or more) if premalignant lesion detected

• Minimum of every 3 months if prior HNSCC

Post-treatment surveillance after treatment for cancer

• Routine follow-up is mandatory – Complete examination of upper aerodigestive

tract mucosa – Chest X-ray annually

• Screening to include gynecological exam in women